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Use of Azathioprine in Adults: Safety

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Use of Azathioprine in Adults: Safety TITLE: Use of Azathioprine in Adults: Safety DATE: 29 August 2014 RESEARCH QUESTION What is the clinical evidence regarding the adverse events associated with the use of azathioprine for any indication? KEY FINDINGS Nine systematic reviews, one randomized controlled trial, and six non-randomized studies included clinical evidence regarding adverse events associated with the use of azathioprine. METHODS A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2014, Issue 8), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. A methodological filter was applied to a focused search (main concept appearing in the title or major subject heading) to limit retrieval to health technology assessments, systematic reviews and meta-analyses. An adverse events filter was applied to a broader search (main concept appearing in the title, abstract or subject heading) to limit retrieval to articles containing safety data. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2009 and August 26, 2014. Internet links were provided, where available. The summary of findings was prepared from the abstracts of the relevant information. Please note that data contained in abstracts may not always be an accurate reflection of the data contained within the full article. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by email or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions. SELECTION CRITERIA Table 1: Selection Criteria Adults (aged 16 to 60 years) who have been prescribed azathioprine for any Population condition/indication Intervention Azathioprine Comparator None; other immunosuppressive agents Outcomes Adverse reactions, adverse events, harms Health technology assessments, systematic reviews, meta-analyses, Study Designs randomized controlled trials, non-randomized studies RESULTS Rapid Response reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials and non-randomized studies. Nine systematic reviews (SR), one randomized controlled trial (RCT), and six non-randomized studies (NRS) included clinical evidence regarding adverse events associated with the use of azathioprine. No health technology assessments were identified. Additional references of potential interest are provided in the appendix. OVERALL SUMMARY OF FINDINGS The summary of adverse events reported in the included studies is grouped below according to disease or procedure. Crohn’s disease Three SRs1,5,9 reported adverse events in patients receiving azathioprine or 6-mercaptopurine (both purine analogues) for Crohn’s disease. All reviews reported adverse events common to treatment with both azathioprine and 6-mercaptopurine: 1,5,9 • leukopenia 1 • arthralgia 1 • abdominal pain or severe epigastric intolerance 1 • elevated liver enzymes 1,5,9 • nausea and vomiting 1,5,9 • pancreatitis 1 • anemia 1 • exacerbation of Crohn’s disease 1 • nasopharyngitis 1 • flatulence 5,9 • allergic reactions Use of Azathioprine in Adults 2 Inflammatory bowel disease Two SRs2,8 reported adverse events in patients receiving azathioprine or 6-mercaptopurine for inflammatory bowel disease (IBD). One NRS16 reported adverse events in patients receiving only azathioprine. Adverse events reported by the studies were: 2 • lymphoma 8 • myelotoxicity 8 • hepatotoxicity 8 • pancreatitis 8 • gastrointestinal intolerance 16 • herpes flares 16 • appearance or worsening of viral warts One SR4 and one NRS13 focused on adverse pregnancy outcomes in patients receiving purine analogues for IBD. The SR4 reported that exposure to either of the drugs in women was associated with preterm birth, but not with low birth weight or congenital abnormalities; and that exposure to the drugs in men at the time of conception was not associated with congenital abnormalities. The NRS13 found that the risk of pregnancy complications was not increased and the drugs seemed to be safe for the newborn. Azathioprine combined with anti-TNF agents for rheumatologic and non-rheumatologic diseases One SR3 reported an increased risk of tuberculosis reactivation when azathioprine was combined with anti-TNF (anti-tumour necrosis factor) agents. Systemic lupus erythematosus (SLE) One SR6 reported that there was an increased rate of hematological cytopenias with azathioprine in patients with SLE. Ulcerative colitis One SR7 and one NRS14 reported adverse events in patients receiving azathioprine or 6- mercaptopurine for ulcerative colitis; one RCT10 reported on adverse events with axothioprine only. Reported adverse events in the studies were: • acute pancreatitis7 • significant bone marrow supression7 • lymphoma14 • serious infection10 Organ transplantation Three non-randomized studies11,12,15 reported adverse events in patients receiving azathioprine following organ transplantation: 11 • increased risk for myelodysplastic syndromes 12 • alternaria infection 12 • fungal skin infection 12 • lymphoproliferative disorder 15 • infectious viral warts Use of Azathioprine in Adults 3 REFERENCES SUMMARIZED Health Technology Assessments No literature identified. Systematic Reviews and Meta-analyses 1. Gordon M, Taylor K, Akobeng AK, Thomas AG. Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease. Cochrane Database Syst Rev. 2014 Aug 1;8:CD010233. PubMed: PM25081347 2. Kotlyar DS, Lewis JD, Beaugerie L, Tierney A, Brensinger CM, Gisbert JP, et al. Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6- mercaptopurine: a meta-analysis. Clin Gastroenterol Hepatol. 2014 May 28. PubMed: PM24879926 3. Lorenzetti R, Zullo A, Ridola L, Diamanti AP, Lagana B, Gatta L, et al. Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a systematic review of randomized controlled trials. Ann Med. 2014 Aug 8;1-8. PubMed: PM25105206 4. Akbari M, Shah S, Velayos FS, Mahadevan U, Cheifetz AS. Systematic review and meta- analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013 Jan;19(1):15-22. PubMed: PM22434610 5. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2013;4:CD000545. PubMed: PM23633304 6. Oglesby A, Shaul AJ, Pokora T, Paramore C, Cragin L, Dennis G, et al. Adverse event burden, resource use, and costs associated with immunosuppressant medications for the treatment of systemic lupus erythematosus: a systematic literature review. Int J Rheumatol [Internet]. 2013 [cited 2014 Aug 28]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638708 PubMed: PM23762067 7. Timmer A, McDonald JW, Tsoulis DJ, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478. PubMed: PM22972046 8. Lopez-Martin C, Chaparro M, Espinosa L, Bejerano A, Mate J, Gisbert JP. Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease. Gastroenterol Hepatol. 2011 Jun;34(6):385-92. PubMed: PM21616565 Use of Azathioprine in Adults 4 9. Prefontaine E, MacDonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2010;(6):CD000545. PubMed: PM20556747 Randomized Controlled Trials 10. Panaccione R, Ghosh S, Middleton S, Marquez JR,
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